Alzheimer's disease (AD) is the major cause of devastating late-life dementia. To date, there are no effective treatments to prevent, cue or even slow the progression of AD, which makes it urgent to identify and evaluate novel therapeutics for AD treatment. It has been suggested that targeting the noradrenergic (NA) system would be beneficial for treatment of AD, given that the NA system plays a critical role in normal cognitive functions, profound loss of NA neurons occurs at the early stage of AD, and evidence from both human patients and animal models indicates that loss of NA innervation greatly facilitates AD pathogenesis and progression. However, the therapeutic potential of targeting the NA system in general, and the adrenergic receptors (ARs) in particular, for AD treatment remains largely unexplored. ARs are mediators of NA transmission and control both NA input to the cerebral cortex and the resulting response in this brain region. Manipulation of AR activity has been shown to regulate neurotransmission, neurogenesis and cognitive behaviors, and thus might impact AD-related pathogenesis and cognitive impairment. The primary objective of this study is to determine the efficacy of adrenergic agents in delaying the onset and slowing the progression of AD using transgenic mouse models. Two aims are proposed as follows. Aim 1 is to determine if adrenergic manipulation delays the onset of AD-related pathology and cognitive deficits. AD transgenic mice and nontransgenic littermate controls will be treated with adrenergic agents or saline starting at 3 months of age, prior to amyloid plaque formation in the transgenic strains. Aim 2 is to determine if adrenergic manipulation slows the progression of AD-related pathology and improves cognitive function. Mice will be treated at 8 months of age, after AD-related pathology and cognitive deficits have developed in the transgenic strains. In both aims, AD-related pathology, neurotransmission and plasticity, and cognitive behaviors will be evaluated as outcomes. This study will provide invaluable preclinical information on the potential use of adrenergic agents to treat AD, and if successful, would open up an entirely new direction for AD treatment. Significantly, a number of adrenergic agents are already widely used clinically. These drugs may be repurposed to treat AD patients, thus saving time and cost associated with new drug development. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the major cause of devastating late-life dementia and currently there are no effective treatments to stop its progression. This study tackles the importance of the adrenergic system in AD pathogenesis, and explores the potential use of adrenergic agents to delay the onset and impede the progression of AD-related pathology and cognitive deficits. If successful, this study would open up an entirely new direction for AD treatment. Significantly, the adrenergic agents which are already used clinically may be repurposed to treat AD patients, thus saving the time and cost associated with new drug development.